Significance

The innate immune system has evolved to protect the host from potential pathogens. The nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome is one of the platforms that can sense pathogenic bacteria, which can cause fatal bacterial infections. Here we show that all three types of bacteria-derived RNA—mRNA, tRNA, and rRNAs—as well as synthetic 20-guanosine ssRNA, are capable of activating the NLRP3 inflammasome and inducing human macrophages to secrete inflammatory cytokines. Interestingly, only bacterial mRNA is able to activate the murine Nlrp3 inflammasome. Therefore human macrophages may have evolved in a unique fashion, adapting to the bacterial environment. This study could provide important clues for developing efficient medicines for bacterial infections and various immunotherapies such as anticancer vaccines.

Abstract

Inflammasomes are multiprotein platforms that activate caspase-1, which leads to the processing and secretion of the proinflammatory cytokines IL-1β and IL-18. Previous studies demonstrated that bacterial RNAs activate the nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome in both human and murine macrophages. Interestingly, only mRNA, but neither tRNA nor rRNAs, derived from bacteria could activate the murine Nlrp3 inflammasome. Here, we report that all three types of bacterially derived RNA (mRNA, tRNA, and rRNAs) were capable of activating the NLRP3 inflammasome in human macrophages. Bacterial RNA’s 5′-end triphosphate moieties, secondary structure, and double-stranded structure were dispensable; small fragments of bacterial RNA were sufficient to activate the inflammasome. In addition, we also found that 20-guanosine ssRNA can activate the NLRP3 inflammasome in human macrophages but not in murine macrophages. Therefore, human and murine macrophages may have evolved to recognize bacterial cytosolic RNA differently during bacterial infections.

Significance

The innate immune system has evolved to protect the host from potential pathogens. The nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome is one of the platforms that can sense pathogenic bacteria, which can cause fatal bacterial infections. Here we show that all three types of bacteria-derived RNA—mRNA, tRNA, and rRNAs—as well as synthetic 20-guanosine ssRNA, are capable of activating the NLRP3 inflammasome and inducing human macrophages to secrete inflammatory cytokines. Interestingly, only bacterial mRNA is able to activate the murine Nlrp3 inflammasome. Therefore human macrophages may have evolved in a unique fashion, adapting to the bacterial environment. This study could provide important clues for developing efficient medicines for bacterial infections and various immunotherapies such as anticancer vaccines.

Abstract

Inflammasomes are multiprotein platforms that activate caspase-1, which leads to the processing and secretion of the proinflammatory cytokines IL-1β and IL-18. Previous studies demonstrated that bacterial RNAs activate the nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome in both human and murine macrophages. Interestingly, only mRNA, but neither tRNA nor rRNAs, derived from bacteria could activate the murine Nlrp3 inflammasome. Here, we report that all three types of bacterially derived RNA (mRNA, tRNA, and rRNAs) were capable of activating the NLRP3 inflammasome in human macrophages. Bacterial RNA’s 5′-end triphosphate moieties, secondary structure, and double-stranded structure were dispensable; small fragments of bacterial RNA were sufficient to activate the inflammasome. In addition, we also found that 20-guanosine ssRNA can activate the NLRP3 inflammasome in human macrophages but not in murine macrophages. Therefore, human and murine macrophages may have evolved to recognize bacterial cytosolic RNA differently during bacterial infections.

bacterial RNA

single-stranded RNA

NLRP3 inflammasome

innate immunity

primary macrophages

Footnotes

↵1To whom correspondence may be addressed. Email: bsun{at}sibs.ac.cn or liuyo{at}medimmune.com.

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